Pediatric Board ReviewEndocrine, Part 4

Anne-Marie Kaulfers, MDPediatric Endocrinology

University of South AlabamaAugust 25, 2011

Overview of calcium metabolismSkinUV light D2 and D3

LiverD2 and D3 25-OH Vit D

Kidney 1-alpha-hydroxylase25-OH Vit D 1,25-OH Vit D

Gut1,25 OH Vit D: Pulls Ca and Phos from food into blood

Overview of calcium metabolismSkinUV light D2 and D3

LiverD2 and D3 25-OH Vit D

Kidney 1-alpha-hydroxylase25-OH Vit D 1,25-OH Vit D

Gut1,25 OH Vit D: Pulls Ca and Phos from food into blood

Regulated by nutrition

Controlled by PTH

Recognize typical lab findings of hypoparathyroidism

• Parathyroid hormone (PTH)– Wants to keep blood calcium levels normal (PTH

couldn’t care less about the bones)– Tells kidney to hold onto calcium and pee out Phos– Tells kidney to make activated Vit D (1,25-OH Vit

D), which goes to the gut and gets the calcium from your food and puts it into your blood

• Lab findings:– Low PTH, Low Calcium, HIGH Phos

Signs and Symptoms of low Ca

• Chvostek’s sign– Tap on cheekbone, and the upper lip will twitch

• Trousseau’s sign– Hand spasm with prolonged BP cuff inflation

• Perioral tingling• Seizures/Psychiatric changes• Papilledema, cataracts, tetany, laryngospasm• Prolonged QT interval on EKG• Low calcium with low phos = vitamin D deficiency

DiGeorge syndrome and low Ca

• Microdeletion of 22q11.2, detected on FISH• CATCH-22• Cardiac abnormalities (aortic arch, etc)• Abnormal facies (small jaw, funky ears)• Thymic aplasia (T-cell related infections)• Cleft palate• Hypocalcemia (no parathyroid gland, so have

low Ca, HIGH Phos, low PTH)

Recognize a child with Pseudohypoparathyroidism

• Resistance of kidney to PTH• (You can make PTH but you can’t use it)• Low Ca, HIGH Phos, but also HIGH PTH• Type 1A is the most common• You inherit this defect from mom• Also have resistance to other hormones

– High TSH, ACTH, LH, and FSH

Recognize a child with Pseudohypoparathyroidism

• Won’t have low calcium until after age 3 years• Seizures in elementary school• Subcutaneous calcifications• Will look fine until after age 1 year, then will

develop: Short stature, obesity, round face, bad teeth, short fingers and toes, joint problems – bowleg, can have MR

• “Albright Hereditary Osteodystrophy”

Causes of low Ca in neonate

In first 2 days of life:• Preemies• Infants with birth

asphyxia/sepsis• Infant of a diabetic

mother– Large for gestational age– Low blood sugar

After first week of life:• High Phosphate load• Low Magnesium• Mom’s

hyperparathyroidism turning off neonatal PTH secretion (check moms PTH level)

• Neonatal Hypoparathyroidism

X-linked (familial) hypophosphatemic rickets: clinical and lab findings

• Bow-legged!!!• Poor growth, bad teeth• Problem: the kidney pees out too much

phosphorus and kidney is never told to make 1,25 OH Vitamin D (aka calcitriol)

• Remember – PTH is only sensitive to calcium• Labs: normal calcium, therefore normal PTH• Labs: low Phos and high Alk Phos• Rickets on Xray

X-linked (familial) hypophosphatemic rickets: treatment

• Phosphorus (Neutra-Phos)• (Cholecalciferol/Ergocalciferol/Calcidiol are all

names of Vitamin D3 or D2, aka 25-OH D)• 1,25 OH Vitamin D (aka calcitriol)

– This goes to the gut and takes the calcium and Phos from your food and puts it into your blood

• Routine monitoring:– Renal U/S looking for stones (from too much Ca)– Serum Alk Phos, goal is to normalize levels

General Causes of Rickets25-OH Vit D

1,25-OH Vit D

Calcium Phos Alk Phos

PTH

Vitamin D Deficiency (nutritional)

↓ ↑

Vitamin D dependent rickets Type 1, 1 alpha - hydroxylase def

(can’t make 1,25 OH Vit D)

↑ ↑

Vitamin D dependent rickets type 2, aka Vitamin D resistant rickets, aka

(resistant to 1,25-OH Vit D)

↑ ↑

X-linked (famlial) hypo-phosphatemic rickets

↑ Nl

Renal disease ↑ ↑

General Causes of Rickets25-OH Vit D

1,25-OH Vit D

Calcium Phos Alk Phos

PTH

Vitamin D Deficiency (nutritional)

↓ NL/↑/↓ ↓ ↓ ↑ ↑

Vitamin D dependent rickets Type 1, 1 alpha - hydroxylase def

(can’t make 1,25 OH Vit D)

↑ ↓ ↓ ↓ ↑ ↑

Vitamin D dependent rickets type 2, aka Vitamin D resistant rickets, aka

(resistant to 1,25-OH Vit D)

NL ↑ ↓ ↓ ↑ ↑

X-linked (famlial) hypo-phosphatemic rickets

NL NL NL ↓ ↑ NL

Renal disease NL ↓ ↓ ↑ ↑ ↑

General Causes of Rickets

• Vit D Deficiency (nutritional): 25OH D is your body’s stores of Vit D. Your liver gives it to the kidney and it gets activated, then it goes to the gut and takes the calcium and phos out of your food and gives it to the blood. So without 25OH, you can’t activate very much, so the blood levels of Ca and Phos stay low. Because Ca is low, PTH goes up.

General Causes of Rickets

• Vitamin D Dependent Rickets Type 1, or 1 alpha hydroxylase deficiency: You can’t make 1,25 OH D, but your bones are sick and hurting so it keeps trying. It stores all the 25OH D that it can, but none of it can get activated, so the 25 OH D levels are high, and 1,25OH D levels are low. You have no activated D to get the Ca and Phos out of your gut and into your blood, so the Ca and Phos levels are low. Because Ca is low, PTH goes up.

General Causes of Rickets

Vitamin D dependent rickets type 2, aka Vitamin D resistant rickets, aka (resistant to 1,25-OH Vit D): These kids have alopecia areata, weird. Anyway, you can store 25-OH D fine, and your kidneys can activate it into 1,25 OH D, but your gut won’t recognize it. So you get high levels of 1,25 OH D, but the Ca and Phos can’t get out of your gut and into your blood, so the blood levels of Ca and Phos are low. Because Ca is low, PTH goes up.

Signs and Symptoms of Hypercalcemia

• Bones, groans, and stones• Weakness, fatigue, decreased appetite,

nausea, vomiting, constipation (abd pain)• Polyuria and polydipsia• Prolonged: can lead to kidney stones, arms

and legs and back pain • Can happen after prolonged immobilization,

too much vitamin A or D, gramulomatous dz

Hypoglycemia in a Young child

• Normal healthy 2-8 year old child• Has symptomatic low blood sugar• Responds easily to IV or oral dextrose• Diagnosis: Idiopathic ketotic hypoglycemia• Test: Check urine for ketones

Hypoglycemia in a young child

• Most common cause: ketotic hypoglycemia• Other causes/tests:

– High insulin but low C-peptide: got an insulin shot– High insulin and high C-peptide: has an insulin tumor

or ate grandma’s sulfonylurea medicine– (Insulin turns off ketones, so a positive urine test for

ketones means that insulin levels are not too high)– Proinsulin: Tells you nothing– Cortisol or growth hormone deficiency

Natural History of type 1 Diabetes

• At diagnosis, still have 20% of beta cells– But they are sick (glucose toxicity prevents them

making insulin)• After a few weeks, these 20% “wake up”• All blood sugars look stable for next weeks to months

to a year: the Honeymoon period. Diabetes seems to be “in remission”, patient may think they are cured.

• Then these 20% of insulin cells finally die off – and blood sugars start to get really high, really fast

Clinical Example

• At diagnosis: A1c is 12%, all BG in hospital are 200’s to 500’s

• 3 months later: All BG are between 60 and 90 mg/dl, even when they drink coke or juice or eat candy or skip shots, A1c is under 6%, patient only needs small amount of insulin

• 6 months later: A1c is 12%, all BG are 200’s to 500’s – honeymoon is over. Increase the insulin doses to normal. STOP DRINKING SWEET TEA

Type 1 diabetesScreening guidelines

• Hypothyroidism (Chronis Lymphocytic Thyroiditis, or Hashimoto’s disease)– TSH every 2-3 years after diagnosis– Weight gain and fatigue– 10% of all kids with type 1 diabetes

• Celiac Disease– TTG antibody at least once after diagnosis– Weight loss, poor growth, big liver– 5% of all kids with type 1 diabetes

Type 1 diabetes mellitusLong Term complications

• Hemoglobin A1c: average BG over 3 months• Microvascular: Retinopathy and Nephropathy• Neuropathy: Peripheral and autonomic• Macrovascular: CAD, stroke, PVD• How to prevent these:

– Good glycemic control– Blood pressure control – No smoking

Basal/Bolus Insulin Dosing

• Basal: insulin needs when you aren’t eating– Lantus (Glargine)

• Bolus: insulin to cover carbohydrates– Humalog (Lispro), Novolog (Aspart)

• Half the daily dose is basal, half is bolus• Insulin pump: uses only Lispro or Aspart• Never use Regular insulin in kids

– Except in insulin gtts in the PICU

Sick Day Management

• ALWAYS NEED INSULIN. Always give insulin.• Don’t hold the insulin!!• When ill, you need energy and electrolytes

(carbs). Need to give insulin for the carbs.• If pump or pump site malfunctions, need to

give a SQ injection of lispro/aspart• If patient is on Glargine and is vomiting but

can sip on Sprite – give insulin for the Sprite

Sick day Management

• Glargine– Lantus– lasts 24 hours – Slow release – Never give it more than

once every 24 hours. – Ok to give even with low

blood sugars

• Lispro/Aspart:– Humalog/Novolog– works immediately – Don’t give if blood sugar

is low – Last 3-4 hours – Can give this as a bolus

every 3-4 hours

Don’t give Regular insulin! If one of the choices on the test asks you to Give regular insulin, it is the wrong answer!

Type 1 Diabetes: DKA

• Electrolyte imbalance before treatment:

• High blood glucose• High potassium• High Phos• Low Bicarb (CO2)

• Electrolyte changes after treatment with IVF and insulin gtt:

• Low blood glucose• Low potassium• Low Phos• Higher bicarb

Type 1 diabetes: Cerebral edema“How to NOT Kill a Diabetic”

Brain

Blood vessel

Correct treatment for DKA: slow rehydration with ½ NS or NS over 24-48 hours

Type 1 diabetes: DKABrain

Blood vessel

Type 1 diabetes: DKABrain

Blood vessel

Type 1 diabetes: DKABrain

Blood vessel

Type 1 diabetes: DKABrain

Blood vessel

Type 1 diabetes: DKATreatment with a big IVF bolus

Brain

Blood vessel

Type 1 diabetes: DKATreatment with a big IVF bolus

Brain

Blood vessel

Type 1 diabetes: DKATreatment with lots of insulin

Brain

Blood vessel

Type 1 diabetes: DKATreatment with lots of insulin

Brain

Blood vessel

Type 1 diabetes: DKA

• You are taking care of a new-onset diabetic – she is 18 months old, initial ph was 6.9 (very low). She is on IVF and an insulin gtt and is doing fine. 6 hours into treatment, mom runs to you panicking that she can’t wake her up, what’s going on and what do you do?

• #1: Decrease the IVF rate and decrease the insulin gtt rate.

• #2: Administer Mannitol

Type 1 diabetes: DKA

• DON’T• EVER• GIVE• BICARB• !!!!!!!!!!

Unless Dr. Vidal tells you to do it, then it is ok

Type 1 vs Type 2 diabetes

• Type 1 • Positive antibodies

– GAD Ab– Anti-islet cell Ab– Insulin autoantibody– Insulinoma 2 associated Ab

• Low C-peptide• + urine ketones/DKA• No acanthosis

• Type 2• NO antibodies• C-peptide +/-

– Usually high, can be low

• Family history +/-• Certain ethnic origin +/-• Urine ketones/DKA +/-• Acanthosis nigricans +/-

Screening for Type 2 diabetes

• It is now ok to use HgbA1c to diagnose diabetes, on board exams and clinically

• Insulin and C-peptide can be variable and high insulin levels don’t mean you have diabetes

• Screen with fasting plasma glucose every 2 years in overwt kids with + fam history or certain ethnic group or + AN

• If fasting glucose is over 110, do a 2 hr OGTT

Treatment for Type 2 diabetes

• Lifestyle modification: Diet and exercise• If no success in a few months, start Metformin• If BG are over 300 and pt also has ketones or

presented in DKA, consider starting insulin• Don’t use any other diabetes drugs – they are

not approved for kids• It is normal for kids with type 2 to already

have CV problems at diagnosis – high BP, low HDL, high LDL, etc

Metabolic Syndrome

• Obesity, high blood pressure, low HDL, high triglycerides, and insulin resistance.

• Acanthosis Nigricans (AN) can be a sign of insulin resistance. It does NOT mean that the patient has high blood sugar or diabetes.

• (PCOS: abnormal menses, clinical signs of excess androgens(hirsute), and cysts on ovary, only need 2 of these)

Metabolic Syndrome

• If your patient has obesity, high BP, low HDL, high triglycerides, and signs of insulin resistance, check for other medical problems:

• Fatty liver – check ALT (transaminase)• PCOS in females – ask about hirsutism, check

free testosterone and DHEA• Look for sleep apnea• Look for microalbuminuria

Recognize hypopituitarism

• Most common acquired cause: craniopharyngioma

• Clinically will see growth failure from GH deficiency and hypothyroid, but it is often missed

• First signs of cranio: visual field defects and headaches. Then growth failure is noticed. Usually patient will be overweight, and have delayed puberty.

Pediatric EndocrinologyPotpourri, Board Review

Anne-Marie Kaulfers, MDPediatric Endocrinology

March 18, 2010

General Growth and Development

• 1A normal newborn weighs 3 kg. How much will he weigh at 3 months of life?

• Actual Numbers:– 0-3 mo: 2 lb and 3.5 cm/month– 3-6 mo: 1.25 lb and 2 cm/month– 6-9 mo: 1 lb and 1.5 cm/month

• Shortcut:– A little less than 1 kg and a little more than 2

cm/month– After age 2 years: 5-8 cm/year is normal

Puberty

• 2A 14 year old boy has testes that are 8 ml. Is this normal, early, or late?

• Ages:– 10 years old: testes are 5 ml– 12 years old: testes are 10 ml– 14 years old: testes are 20 ml

Puberty

• 3A 10 year old boy is Tanner 2. What size are his testes?

• Tricks to remember:– Multiply by 3– Tanner 2: size 6 ml– Tanner 3: size 9 ml– Tanner 4: size 12 ml– Tanner 5: size 15 ml

Puberty

• 4A 16 year old boy is really short, testes are 15 ml. Has he had a growth spurt yet/will he get much taller?

• Testicular Size– Sizes 1-25 ml– 4: start of puberty– 10: start of growth spurt– 20: adult size

Puberty – Gynecomastia

• 5A very tall 17 y/o boy has bilateral breast tissue and small testes. What genetic syndrome does he have?

• Other features:– Learning disability– Behavior disorder/ADHD– 47, XXY– Low testosterone, High LH and FSH

Delayed puberty

• 6A 15 y/o boy is seen for delayed puberty. He has a normal height and has Tanner 5 body hair, but his testes are only 2 ml. He has a history of a cleft lip repair, and only has one kidney. He gets extra help in school because of mild MR. You check labs and his LH, FSH, and testosterone levels are all low. What genetic syndrome does he have?

• What if I tell you he also can’t smell?

Growth• 7They show a picture of a normal appearing girl who

they tell you is short. What is the diagnosis?• 8What autoimmune disease is she at risk for?• 9What imaging studies are needed at diagnosis?• Other things to consider:

– Can start GH after age 9 months– Needs hearing and eye evaluation– May develop scoliosis, teeth problems– May have a nonverbal learning disorder– Start estrogen at 12 years– If has a mosaic karyotype including a Y (XO/XYY), need to

remove the gonads due to risk for gonadoblastoma

Brain abnormalities

• 10A newborn baby has nystagmus. MRI reveals optic nerve hypoplasia with absent septum pellucidum. What endocrine problem do you consider?

• 11A newborn baby has a micropenis. What diagnosis do you consider?

• 12A baby has a single central incisor. What diagnosis do you consider?

Adrenoleukodystrophy• Only happens in boys (X-linked)• At age 3-4 years, they get progressive behavior

problems: aggression, hyperactivity, poor memory, poor handwriting.

• Then it progresses to ataxia, increased spasticity, blind, deaf, then can’t speak or swallow. Interval from 1st sign to complete vegetative state is 2 years, followed by death.

• They also get N/V, fatigue, low BG, muscle weakness from adrenal insufficiency

• Test: VLFCA (very long chain fatty acids)

Hypo/Hyperphosphatasia• Hypophosphatasia:

– Low levels of Alk Phos– Usually fatal in infancy– Leads to osteomalacia and bad periodontal dz

• Hyperphosphatasia:• “Transient”:

– very high Alk Phos with no liver or bone disease,– resolves in months with no tx. – usually kid is under age 5 years and is healthy

• Permanent: look for underlying bone and liver dz

Lab tests

• 13A known diabetic comes into the ER in DKA. Initial BG is 600 mg/dl, and the sodium level on the blood work reads 140 mmol/L. What is the real sodium level?

• High glucose falsely lowers the sodium. For every 100 mg/dl the glucose is over normal, the sodium level decreases by 1.6 mmol/l.

Lab tests - Growth• 14What lab tests do you use to screen for

growth hormone deficiency?• 15If IGF-1 and IGF-BP3 are low, what test do

you do to confirm growth hormone deficiency?

• 16Which lab test do you use to monitor the patient once they are on GH therapy?

• 17What are some side effects of GH therapy?• 18What agents are used for GH stimulation

testing?

Other tests for growth

• If overweight:• Hypothyroid

– TSH and free thyroxine

• GH deficiency– IGF1 and IGF-BP3

• Cushing’s syndrome– 24 hr urine free cortisol

• If underweight:• GI disease

– Crohn’s– ESR

• Renal disease (RTA)– Chem-8

• Celiac disease– Tissue tranglutaminase

Indications for Growth Hormone

• Growth Hormone deficiency

• Hypopituitarism• Panhypopituitarism• Turner’s syndrome• Noonan’s syndrome• Prader Willi syndrome

• AIDS wasting• Chronic renal

insufficiency/failure• Born SGA or IUGR with

failure of catch-up growth by age 2 years

• Idiopathic Short Stature• SHOX gene deficiency

Lab tests - Puberty

• 19A little 5 y/o girl has breast development and accelerated height velocity. What stimulation test do you use to evaluate for precocious puberty?

• 20Once central precocious puberty is confirmed, what imaging study do you do next?

• 21What brain lesion causes precocious puberty and gelastic seizures (aka laughing fits)?

Pre-Puberty

Hypothalamus

Pituitary

Ovary/Testes

GnRH pulses

LH, FSH

Puberty

Hypothalamus

Pituitary

Ovary/Testes

GnRH pulses

LH, FSH

Early Puberty:Before age 7 in black girlsBefore age 8 in white girlsBefore age 9 in boys

Precocious puberty

• 22A 15 y/o girl moves to the USA from an underdeveloped country with poor health care. She is very short and she started her periods when she was 4 years old. On physical exam, you notice many café-au-lait spots with irregular borders: a “coast of Maine” appearance. One arm is longer than the other and she has a strange bony overgrowths on her face. What syndrome does she have?

McCune-Albright syndrome

• Peripheral precocious puberty• Café-au-lait spots•Polyostotic fibrous dysplasia

•Bone is replaced by fibers

Polycystic ovarian syndrome

• Oligo – or an- ovulation• Clinical or biochemical evidence of

hyperandrogenism• Polycystic ovaries on ultrasound

• Need 2 out of these 3 to make a diagnosis– Increased risk of metabolic syndrome

• Obesity, high trig, low HDL, high BP, high fasting BG

PCOS – clinical picture

High:• Free Testosterone• Androstendione• DHEA• DHEA-S• Insulin• Total Testosterone (or nl)• LH• LH/FSH ratio > 3 (or nl)

Low:• Sex-hormone

binding globulin• FSH

Mostly obese – some have metabolic syndromeSome have polycystic ovaries on U/S

Hirsutism(Clinical evidence of hyperandrogenism/PCOS)

• Male pattern hair in women• Hairs are long, dark, curly: “terminal” • On Upper lip, chin, upper chest, abd, back• The degree of hirsutism is NOT directly related to the

levels of androgens in the blood• Hirsutism doesn’t indicate pathology• Diff from virilization:

– Clitiromegaly, male body shape, male-pattern baldness, voice deepening

– Needs a more complete workup

Amenorrhea

• No menses 4 yrs after breast dev• No menarche by age 16 years• Delayed puberty: no signs by age 14 yrs• Secondary: missing 3 cycles of menses• Anovulation:

– Major cause of amenorrhea– Happens to most girls in 1st 2 yrs of menses– Can still be happening at 5 yrs post-menses

Hypothalamic amenorrhea• Low GnRH: leads to low LH and low FSH

– Stress– Exercise– Poor nutrition (eating disorders)– Athlete triad: disordered eating, amenorrhea, osteoporosis– Weight changes– Extreme emotion– Drugs: heroin, methadone– Chronic Disease: CF, renal dz– Genetic: Kallman’s, Prader-Willi, Bardet-Biedl– High Prolactin– Thyroid dysfunction

Prolactin

• Clinical picture of a prolactinoma:– Galactorrhea (variable)– Headache– Visual field deficit– Infertility/irregular periods– Osteopenia (from low estrogen levels)

• Only ½ will have a mass on MRI– Microadenoma: <10 mm (Macro >10 mm)

Lab tests - Adrenal

• Newborn baby has congenital adrenal hyperplasia.

• First lab to check:– 17-hydroxyprogesterone

• Most likely adrenal enzyme deficiency: – 21 alpha hydroxylase

• Test to confirm the diagnosis:– ACTH stimulation test

Tests - Thyroid

• Different names:• TSH and thyrotropin• T4 and thyroxine and levothyroxine• T3 and triiodothyronine and Cytomel• Don’t treat with T3 or measure T3

Water Hormones

Diabetes Insipidus• Can’t make ADH• Pee out all your water• Only thing left in blood is salt• Only thing in your pee is water• Can’t concentrate the urine• Patient pees too much, so therefore they drink

Diabetes Insipidus - Labs

• High serum Na• High serum Osm• Low spec grav in urine• Low urine osmolarity• polyuria/polydipsia, even overnight• Patient prefers only water, cold water• Confirm with water deprivation test• Treat with DDAVP (vasopressin)

Diabetes Insipidus - Testing

• Confirm with a water deprivation test• Admit kid to hospital, no eating or drinking• When serum Na goes above 140 and serum

osm goes above 300 and urine is still dilute, you have confirmed DI

• Then give vasopressin (DDAVP)– Central DI: urine will concentrate (urine osm >600)– Nephrogenic DI: urine will stay dilute

• Treatment: low salt diet and a thiazide diuretic

SIADH

• You make too much ADH, so you can’t pee out your water.

• Only thing in the pee is salt• The blood is mostly water• Happens after brain injury• Urine: high sodium, high osm, high SG• Blood: low Na, low osm• Treatment: water restriction

23What heart lesion do these girls have?

I see full cheeks and a large mouth

24What heart lesion do these girls have?

Answers• 1: He will weigh 5.4 kg• 2: Late• 3: Testes are 6 ml.• 4: No, he has finished growing.• 5: Klinefelter’s• 6: Kallmann’s syndrome• 7: Turner’s syndrome• 8: Hypothyroidism, and also celiac• 9: Get a heart Echo and renal ultrasound• 10-12: hypopituitarism• 13: Sodium level is 148.

Answers• 14: IGF-1 and IGF-BP3• 15: growth hormone stimulation test, with two agents: arginine,

clonidine, L-dopa, or insulin• 16: IGF-1• 17: headache (increased ICP), SCFE, high blood sugar • 18: Clonidine, Arginine, L-Dopa, Glucagon, Insulin• 19: leuprolide stimulation test• 20: MRI of the brain• 21: hypothalamic hamartoma• 22: McCune-Albright syndrome• 23: Williams syndrome – supravalvular aortic stenosis• 24: Turner’s syndrome – coarctation of the aorta and bicuspis aortic

valve